Co-Authors:
Hammes, H.-P., Fifth Medical Clinic, Medical Faculty, University of Heidelberg, Mannheim, Germany, Fifth Medical Clinic, Medical Faculty, University of Heidelberg, Theodor -Kutzer-Ufer 1-3, D-68135 Mannheim, Germany
Lin, J., Fifth Medical Clinic, Medical Faculty, University of Heidelberg, Mannheim, Germany
Renner, O., Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
Shani, M., Institute of Animal Science, Volcani Center, Bet, Dagan, Israel
Lundqvist, A., Department of Medical Biochemistry, Goteborg University, Gothenburg, Sweden
Betsholtz, C., Department of Medical Biochemistry, Goteborg University, Gothenburg, Sweden
Brownlee, M., Albert Einstein College of Medicine, New York, NY, United States
Deutsch, U., Max-Planck Institute for Vascular Biology, Münster, Germany
Abstract:
Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B+/- mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B+/- mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B+/- mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B+/- mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B+/- mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.